Lower 5-hydroxyindoleacetic Acid Research Articles

Environmental enrichment induces changes in brain monoamine levels in gilthead seabream Sparus aurata

It is generally accepted that environmental enrichment enhances the performance and improves welfare of animals kept in captivity. Similar results have been obtained for fish. It has been previously reported that the presence of Blue or Red-Brown Substrate (BS and RBS respectively) on tank bottom resulted in growth enhancement and suppression of aggressive behavior of gilthead seabream Sparus aurata compared to Green Substrate (GS) and tanks without modifications (Control-C). In an attempt to identify the underlying mechanisms, in the present study the effects of this environmental enrichment on brain monoamine neurotransmitters and fatty acids of gilthead seabream were evaluated. BS and RBS fish had lower serotonergic activity (5-HIAA/5-HT), resulting mainly from lower 5-hydroxyindoleacetic acid (5-HIAA) levels. BS fish also had lower serotonin levels compared to all other treatments. Brain noradrenaline (NA) levels did not show significant differences between substrate treatments and control. Brain dopamine (DA) levels were lowest in BS and RBS fish, higher in GS fish and highest in C fish. No differences were observed for dopamine metabolites or dopaminergic activity. Moreover, brain NA was negatively correlated with body weight in BS fish and positively correlated in RBS and C fish. A positive correlation was also observed for brain DA with body weight in RBS fish. No differences were observed for brain fatty acids. Present results support the hypothesis that the beneficial effects of the presence of BS and RBS are related to altered social interactions and indicate the establishment of a less stressful social organization in enriched-reared fish groups.

Autosomal dominant tauopathy with parkinsonism and central hypoventilation

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T) can show various clinical phenotypes.1 We describe Japanese siblings with the intronic 10 + 14 splice site mutation of the microtubule-associated protein tau (MAPT) gene, showing parkinsonism, depression, weight loss, and central hypoventilation with reduced serotonin concentration suggested by low 5-hydroxyindole acetic acid (5-HIAA) in CSF. These clinical and biochemical features are just shared by Perry syndrome,2–4 although neither DCTN1 gene mutation nor TDP-43 proteinopathy was found. ### Case reports. A Japanese woman (III-5) (figure, A) developed clumsiness, tremor of the upper limbs, appetite loss, and apathy at age 44. She had lost 14 kilograms of body weight during 10 months. Mask-like face, hypophonic voice, bradykinesia, and muscle rigidity with predominance on the right side were observed. Deep tendon reflexes were hyperactive, especially in the right extremities with the Babinski sign. Despite levodopa treatment, her parkinsonism progressed and memory loss, disorientation, and cyanosis became apparent. Blood tests, EKG, and chest X-ray were not remarkable. Arterial blood gases showed reduced oxygen (60.3 Torr) and increased carbon dioxide (55.5 Torr). CSF analysis showed reduced 5-HIAA (5.6 ng/mL [normal 28.5 ± 7.2 ng/mL]). Brain MRI demonstrated mild atrophy in the brainstem tegmentum. Polysomnography revealed central hypoventilation with hypoxia. Although memory loss, disorientation, and …

Fluoxetine induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats

Fluoxetine (FLX) is a drug commonly used as antidepressant. However, its effects on tumorigenesis remain controversial. Aiming to evaluate the effects of FLX treatment on early malignant changes, we analyzed serotonin (5-HT) metabolism and recognition, aberrant crypt foci (ACF), proliferative process, microvessels, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) expression in colon tissue. Male Wistar rats received a daily FLX-gavage (30mgkg−1) and, a single dose of 1,2 dimethylhydrazine (DMH; i.p., 125mgkg−1). After 6 weeks of FLX-treatment, our results revealed that FLX and nor-fluoxetine (N-FLX) are present in colon tissue, which was related to significant increase in serotonin (5-HT) levels (P<0.05) possibly through a blockade in SERT mRNA (serotonin reuptake transporter; P<0.05) resulting in lower 5-hydroxyindoleacetic acid (5-HIAA) levels (P<0.01) and, 5-HT2C receptor mRNA expressions. FLX-treatment decreased dysplastic ACF development (P<0.01) and proliferative process (P<0.001) in epithelia. We observed a significant decrease in the development of malignant microvessels (P<0.05), VEGF (P<0.001), and COX-2 expression (P<0.01). These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue, probably due to its modulatory activity on 5-HT metabolism and/or its ability to reduce colonic malignant events.

Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants

The known Gly56Ala mutation in the serotonin transporter SERT (or 5-HTT), encoded by the SLC6A4 gene, causes increased serotonin reuptake and has been associated with autism and rigid–compulsive behavior. We report a patient with macrocephaly from birth, followed by hypotonia, developmental delay, ataxia and a diagnosis of atypical autism (PDD-NOS) in retrospect at the age of 4½ years. Low levels of the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in CSF were detected, and SLC6A4 gene analysis revealed the heterozygous Gly56Ala alteration and the homozygous 5-HTTLPR L/L promoter variant. These changes are reported to be responsible for elevated SERT activity and expression, suggesting that these alterations were responsible in our patient for low serotonin turnover in the central nervous system (CNS). Daily treatment with 5-hydroxytryptophan (and carbidopa) led to clinical improvement and normalization of 5HIAA, implying that brain serotonin turnover normalized. We speculate that the mutated 56Ala SERT transporter with elevated expression and basal activity for serotonin re-uptake is accompanied with serotonin accumulation within pre-synaptic axons and their vesicles in the CNS, resulting in a steady-state of lowered serotonin turnover and degradation by monoamine-oxidase (MAO) enzymes in pre-synaptic or neighboring cells.

Cholesterol, CSF 5-HIAA, violence and intent in suicidal men

Associations between suicide, violent behaviour and both hypocholesterolaemia and low 5-hydroxyindolacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) have been suggested. The relationships between lipids, the serotonergic system, suicidal and aggressive behaviors are complex. We explored relationships between serum cholesterol, CSF 5-HIAA, the planning subscale of suicide intent and violence of attempted suicide method in 13 medication-free male suicide attempters and eight healthy volunteers. Serum high-density lipoprotein cholesterol (HDL-C) levels were significantly lower in suicide attempters than in controls. HDL-C showed a significant positive correlation with the planning subscale of suicide intent in non-violent suicide attempters. A positive association was observed between CSF 5-HIAA and serum cholesterol in suicides. The role of cholesterol may be different in planned non-violent suicide attempts compared with violent suicide attempts.

Cerebrospinal fluid monoamine metabolites and suicide

Prospective studies of the serotonergic system and suicide report that low 5-hydroxyindolacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) and a history of attempted suicide predict suicide risk. Low CSF homovanillic acid (HVA) is reported to be associated with past and future lethality of suicide attempts but not with suicide. The interrelationships between monoamine metabolites, violent method, suicide intent and lethality of suicidal behaviour are complex. We hypothesized that CSF 5-HIAA and HVA levels are related to suicide intent, violence and lethality of suicidal behaviour. Fifteen male suicide attempters admitted to a psychiatric ward at the Karolinska University Hospital and eight healthy male volunteers were submitted to lumbar puncture and CSF 5-HIAA and HVA were assayed. Suicide intent with the Beck Suicide Intent Scale (SIS), lethality and violence of suicidal behaviour were assessed. All patients were followed up for causes of death. Six suicides and one fatal accident were identified with death certificates. Mean CSF 5-HIAA but not CSF HVA differed between suicides and survivors. Violent suicides had higher suicide intent and CSF 5-HIAA than non-violent suicides. In violent suicides, CSF 5-HIAA levels were negatively correlated with SIS. Greater suicide intent may be associated with greater aggressive intent and predicts a violent suicide method.

CSF 5-HIAA and DST non-suppression — Orthogonal biologic risk factors for suicide in male mood disorder inpatients

Two biomarkers of suicide risk; non-suppression in the dexamethasone suppression test (DST) and low 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) have been reported to be predictors of suicide in mood disorders. The interrelation of the two systems seems to be different in suicide attempters compared with depressed inpatients who have not made a suicide attempt, indicating that the two biomarkers may be seen as independent. This investigation examined the interrelation of low CSF 5-HIAA and DST non-suppression in suicide victims with mood disorder. Fifty-eight mood disorder inpatients not receiving any treatment with antidepressants underwent lumbar puncture and the DST. Plasma cortisol levels at 8:00 a.m., 4:00 p.m. and 11:00 p.m. were analysed in relation to CSF 5-HIAA. All patients were followed up for causes of death and suicides were verified with death certificates. During follow-up (mean 21 years), 11 (19%) patients had committed suicide. In male suicide victims ( n = 6), the serum cortisol level at 4:00 p.m. showed a significant positive correlation with CSF 5-HIAA. Low CSF 5-HIAA predicted all early suicides (within 1 year), whereas all males who committed suicide after 1 year were DST non-suppressors. In female suicide victims ( n = 5), the post-DST serum cortisol did not correlate with CSF 5-HIAA. Low CSF 5-HIAA and DST non-suppression are orthogonal biologic risk factors for suicide in male mood disorder inpatients. CSF 5-HIAA is associated with short-term suicide risk; dysregulation of the hypothalamic-pituitary-adrenal axis seems to be a long-term suicide predictor.

Mitochondrial diseases mimicking neurotransmitter defects

Objectives Mitochondrial disorders are clinically heterogeneous. We aimed to describe 5 patients who presented with a clinical picture suggestive of primary neurotransmitter defects but who finally fulfilled diagnostic criteria for mitochondrial disease. Methods We report detailed clinical features, brain magnetic resonance findings and biochemical studies, including cerebrospinal fluid (CSF) biogenic amine and pterin measurements, respiratory chain enzyme activity, and molecular studies. Results The 5 patients had a very early onset age (from 1 day to 3 months) and a severe clinical course. They all showed a clinical picture suggestive of infantile hypokinetic-rigid syndrome (hypokinesia, hypomimia, slowness of reactions, tremor), other abnormal movements (myoclonus, dystonia), axial hypotonia, limb hypertonia, feeding difficulties, and psychomotor delay. Abnormal CSF findings among the 4 patients without treatment included low levels of homovanillic acid (HVA) in 3 patients, with associated low 5-hydroxyindoleacetic acid (5-HIAA) concentrations in two of them. Absent or mild and transitory improvement was observed after treatment with l-dopa. A diagnosis of mitochondrial disorder was finally made due to the appearance of hyperlactacidemia, diverse respiratory chain defects, and multisystemic involvement. Conclusions Secondary neurotransmitter disturbances may occur in mitochondrial diseases. Differential diagnosis of hypokinetic-rigid syndrome presenting in infancy could also include paediatric mitochondrial disorders.

CSF 5-HIAA and DST non-suppression -independent biomarkers in suicide attempters?

Background Two major biomarkers of suicidal behaviour; low 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) and non-suppression in the dexamethasone suppression test (DST) have evidence for predictive power for suicide in mood disorders. Previous suicide attempt is the most robust clinical risk factor. Purpose of study To study the interrelationship of suicide risk factors: low CSF 5-HIAA and the DST non-suppression in mood disorder patients with and without an index suicide attempt. Methods Fifty-eight hospitalised mood disorder patients (twenty-five with an index suicide attempt), who were not receiving any treatment with antidepressants, underwent lumbar puncture and DST. Plasma cortisol levels were determined from blood samples drawn the following day at 8:00 a.m., 4:00 p.m. and 11:00 p.m. and analysed in relation to CSF 5-HIAA. Results In the sample as a whole, the serum cortisol level at 4:00 p.m. showed a significant positive correlation to CSF 5-HIAA ( r = 0.3, p < 0.02). In the patients with an index suicide attempt, the serum cortisol at 4.00 p.m. correlated positively with CSF 5-HIAA ( r = 0.65, p < 0.0006), but not in the non-attempters (NS). Conclusion The positive correlation means that low CSF 5-HIAA and DST non-suppression are relatively independent biomarkers of suicide risk in suicide attempters. The interrelation of the two systems seems to be different in suicide attempters compared to depressed inpatients without suicide attempt.

Differential autonomic nervous system response in obese and anorexic chickens ( Gallus gallus)

Effect of reserpine on body weight (BW), feed intake (FI), brain and plasma catecholamine and indoleamine concentrations in high- (HWS) and low- (LWS) weight selected lines of chickens was investigated. Chicks from each line were assigned to three treatment groups and injected intraperitoneally with 0, 1.25, or 2.50 mg/kg of reserpine at hatch, and again at 5 weeks-of-age. Chick BW and FI were determined weekly. At 7 weeks-of-age, 12 males and females from each group were sacrificed for neurotransmitter analysis. In the HWS line there was a dose-dependent decrease in BW through 7 weeks-of-age, whereas in the LWS line BW decreased only through the first 2 weeks-of-age. In the LWS line, norepinephrine (NE), epinephrine, and 3,4-dihydroxyphenylacetate concentrations decreased in the brain in a linear and quadratic manner in response to reserpine, but not in the HWS line. Both lines showed linear decreases in dopamine levels in response to reserpine; however, serotonin was not affected by reserpine. Chickens in the HWS line had greater plasma NE, and lower 5-hydroxyindoleacetic acid than those in the LWS line. In conclusion, it appears that chickens from the HWS line were more sensitive to the BW reducing effects of reserpine than those from the LWS line, with the latter appearing to have greater sympathetic nervous system activity.

Altered serotonin function in suicide. Evidence from platelet and neuroendocrine studies.

Significant progress has been made in understanding psychosocial, psychological, and environmental factors associated with suicide; however, it is only recently that attention has been paid to the understanding of the neurobiology of suicide. There are several studies that implicate the serotonin (5-HT) system in suicide. Initial evidence was obtained from observations of low 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) of depressed patients with a previous history of suicide attempts. Several strategies have been used to examine the serotonergic system in suicidal behavior, which include the determination of serotonin and its metabolites in CSF and postmortem brain tissues as well as serotonin receptor subtypes in postmortem brain tissues, and in platelets of suicidal patients. The neuroendocrine strategy, often termed the "window to the brain," has been extensively used for studying the serotonergic system in suicide. This chapter will review the results obtained from neuroendocrine and serotonin studies in platelets. Initial studies in platelets focussed on determining serotonin uptake and serotonin transporter binding sites in platelets of depressed and suicidal patients. Whereas several studies have found decreased imipramine binding sites of platelets of depressed patients, imipramine binding sites in platelets of suicidal patients showed inconsistent results. Similarly, no consistent changes in 5-HT uptake have been observed in platelets obtained from suicidal patients compared to nonsuicidal patients. On the other hand, studies of platelet 5-HT2A receptors appear to be quite encouraging. Initially, several investigators indicated that they found an increase in platelet 5-HT2A receptors in depressed patients. Subsequently, it was shown that platelet 5-HT2A receptors in suicidally depressed patients were significantly higher compared to nonsuicidally depressed patients and normal control subjects. It has also been shown that platelet 5-HT2A receptors are increased in suicidal patients independent of diagnosis, similar to platelets. 5-HT2A receptors have also been shown to be increased in the postmortem brain of suicide victims by several investigators, although some investigators do not find such an increase. The neuroendocrine strategy provides an important method for studying serotonin function in the central nervous system of depressed and suicidal patents. Using a serotonergic probe of 5-HT1A receptors, several investigators examined ipsapirone-induced prolactin release in suicidal patients and did not find it different that that of control subjects. On the other hand, fenfluramine, which causes release of serotonin and blocks serotonin uptake, causes a decreased release of prolactin in depressed patients compared to normal control subjects. Furthermore it has been shown by some investigators that fenfluramine-induced prolactin release is also decreased in suicidal patients compared to normal control subjects. In summary, platelet and neuroendocrine studies have provided initial evidence sufficient to suggest serotonergic abnormalities in suicidal patients. Most earlier evidence is based on CSF 5-HIAA studies, but it appears that 5-HT2A receptors in both platelet and postmortem brain samples are increased in suicidal patients. The observation that platelet 5-HT2A receptors are increased in suicidal patients independent of diagnosis provides a very useful potential biological marker for identifying suicidal patients.

Dopaminergic and serotonergic function following isolation rearing in rats: Study of behavioural responses and postmortem and in vivo neurochemistry

This series of experiments compared isolation-reared and socially reared rats for their locomotor activity, behavioural stereotypy, and monoamine function both postmortem and in vivo using intracerebral dialysis. In Experiment 1, isolates showed an altered time course of locomotor activity following d-amphetamine sulphate (AMPH) administration (0.5, 2.0, 3.0, or 5.0 mg/kg, SC). Isolation-reared rats also showed increased sensitivity to the sedative effects of a low dose of apomorphine hydrochloride (0.1 mg/kg) but did not differ from social controls following higher doses of the drug (0.5, 1.5, or 3.0 mg/kg, SC). Isolates showed a decrease in the intensity of apomorphine-induced stereotyped behaviours but no change in stereotypy induced by AMPH. In Experiment 2, isolates had higher postmortem dopamine (DA) concentrations and an altered symmetry in DA function in the medial prefrontal cortex (PFC) but not in the nucleus accumbens (NAC) or caudate putamen (CPu). Isolated rats also had a lower 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratio in the NAC (but not in the PFC or CPu) compared to controls. Experiment 3 used intracerebral dialysis to examine monoamine function in vivo following isolation rearing. Isolates showed greater increases in extracellular DA and greater decreases in DOPAC in response to 2 mg/kg AMPH SC in both the NAC and CPu. There were no apparent differences in the perfusate concentrations of either dopamine (DA), dihydroxyphenylacetic acid (DOPAC), or homovanillic acid (HVA) prior to drug administration. However, consistent with the results of Experiment 2, isolates had a reduced basal perfusate concentration of 5-HIAA from the NAC but not from the CPu. Experiment 4 measured postsynaptic DA function in CPu tissue slices following isolation. Isolation rearing did not affect cAMP accumulation in response to stimulation of D 1 DA receptors by DA (0, 2.7, 9, or 30 μM). In addition, isolation rearing did not affect the coupling between D 1 and D 2 receptors, as measured by the increase in cAMP accumulation with 1 μM 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1 H-3-benzazepin (SK&F 38393) and its reduction by 10 μM quinperole hydrochloride (LY 171555). These results are discussed in terms of the possible relationship between these neurochemical findings and the behavioural disturbances following isolation rearing of rats.

Dissociation of serotoninergic and dopaminergic components in acute effects of 1-methy 1-4-pheny 1-1,2,3,6-tetrahydropyridine in mice

Behavioural and neurochemical effects of acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in mice have been studied in order to determine the change in the neurotransmitter profile of the following areas of the brain: substantia nigra (SN), nucleus caudatus putamen (NCP), limbic system (LS tuberculum olfactorium and nucleus accumbens), medulla oblongata (MO) and cerebellum (CER). Subcutaneous administration of MPTP (40 mg/kg) caused behavioural syndromes including restlessness, straub tail, hindlimb abduction, tremor, jumping, bradykinesia and akinesia in Balb/c mice. There existed a well-defined biphasic profile of motor activity comprising of an initial excitatory phase followed by an inhibitory phase lasting about two and a half and five hours, respectively. A significant rise in 5-hydroxytryptamine (5-HT) content together with a decreased 5-HT utilization as evidenced by lower 5-hydroxyindole acetic acid (5-HIAA) to 5-HT ratio in the above brain areas demarcated the excitatory phase, whereas the inhibitory phase was distinguished by a significant decrease in dopamine (DA) content along with an increased turnover of the amine as shown by a higher homovanillic acid (HVA) to DA ratio in the functionally important nuclei of the extrapyramidal system like SN, NCP and LS. Methysergide, a nonspecific 5-HT receptor blocker, but not ketanserin, a specific 5-HT 2 antagonist, prevented the occurrence of the initial excitatory phase without affecting the depressive phase. Administration of apomorphine, a dopamine agonist, 30 minutes prior to MPTP was ineffective, whereas its application 90 minutes after MPTP prevented the occurrence of bradykinesia and akinesia. Interestingly, treatment with haloperidol, the dopamine ( D 1 D 2 ) antagonist, before and after MPTP administration caused an early onset and prolongation of the inhibitory phase without affecting the initial hyperexcitement. The results provide direct evidence for the involvement of Serotoninergic and dopaminergic mechanisms in the genesis of the early and late syndromes of acute MPTP poisoning respectively.

Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentration differentiates impulsive from nonimpulsive violent behavior

Relationships of impulsive and nonimpulsive violent behavior to cerebrospinal fluid (CSF) monoamines and their metabolite concentrations were studied in thirty-six violent offenders. A relatively low 5-hydroxyindoleacetic acid (5HIAA) concentration was found in the CSF of impulsive violent offenders. This was not true for the offenders who had premiditated their acts. Other CSF monoamine or metabolite concentrations were not significantly different between the two groups. Of the groups studied, impulsive violent offenders who had attempted suicide had the lowest 5HIAA levels. A low CSF 5HIAA concentration may be a marker of impulsivity rather than violence.